Author Lizelle T. Fox, Minja Gerber, Josias H. Hamman
transdermal route of administration offers an alternative pathway for systemic drug delivery with numerous advantages over conventional routes. Regrettably, the stratum corneum forms a formidable barrier that hinders the percutaneous penetration of most drugs, offering an important protection mechanism to the organism against entrance of possible dangerous exogenous molecules. Different types of penetration enhancers have shown the potential to reversibly overcome this barrier to provide effective delivery of drugs across the skin, physical skin penetration enhancers are already employed by the pharmaceutical industry, skin penetration enhancers are associated with irritating and toxic effects. This emphasizes the need for the discovery of new, safe and effective skin penetration enhancers. Penetration enhancers from natural origin have become popular as they offer several benefits over their synthetic counterparts, The skin, as the largest organ of the body, serves as a protective layer of the underlying tissues such as muscles, ligaments and internal organs, shielding it from exogenous molecules as well as from mechanical and radiation-induced injuries. The skin also plays a role in immunology and metabolism, regulates body temperature, serves as an excretory organ through sebaceous and sweat glands and contains sensory nerve endings for the perception of touch, temperature, pain and pressure. The skin varies in color, thickness and presence of nails, hairs and glands between the different regions of the body, although all types of skin have the same basic structure, The external surface of the skin is called the epidermis and consists of keratinized squamous epithelium. The next layer is the highly vascular dermis that nourishes and supports the epidermis and consists of a thick layer of dense, fibroelastic connective tissue which contains many sensory receptors. Underlying the dermis is the subcutaneous layer (or hypodermis) comprising of variable amounts of adipose tissue, the skin has been investigated as a route to deliver drugs topically, regionally or systemically, but unfortunately dermal and transdermal drug delivery is often limited by poor drug permeability , this low permeability can be mainly attributed to the most outer layer of the skin, called the stratum corneum, which serves as a rate-limiting lipophilic barrier against the uptake of chemical and biological toxins and the loss of water, epidermal cell membranes are so tightly joined that there is hardly any intercellular space through which polar non-electrolyte molecules and ions can diffuse [8]. The proteins and lipids of the stratum corneum form a complex interlocking structure, resembling bricks and lipid mortar, the major lipids found in the stratum corneum include cholesterol and fatty acids, Ceramides, in particular ceramide 2 and ceramide 5, play an important role in the stratum corneums overall lipid matrix organization and skin barrier function, the ceramides are tightly packed in lipid layers due to the strong hydrogen bonding between opposing amide headgroups. This indicates a transverse organization in addition to the lateral orthorhombic chain organization of ceramide molecules, this hydrogen bonding is responsible for the strength, integrity and barrier properties of the lipid layers in the stratum corneum, the different routes by which a molecule can cross the stratum corneum include the transcellular, intercellular and appendageal (i.e., through the eccrine/sweat glands or hair follicles) routes, the latter route is, however, considered to be insignificant partially due to the appendages occupying only a relatively low surface area corneums overall lipid matrix organization and skin barrier function , the ceramides are tightly packed in lipid layers due to the strong hydrogen bonding between opposing amide headgroups., this indicates a transverse organization in addition to the lateral orthorhombic chain organization of ceramide molecules. hydrogen bonding is responsible for the strength, integrity and barrier properties of the lipid layers in the stratum corneum, the different routes by which a molecule can cross the stratum corneum include the transcellular, intercellular and appendageal (i.e., through the eccrine/sweat glands or hair follicles) routes , The latter route is, however, considered to be insignificant partially due to the appendages occupying only a relatively low surface area This causes the range of potential drugs that can be administered transdermal to be very small, which highlights the need for incorporation of penetration enhancers into formulations that could assist in the effective delivery of a larger variety of drugs [5]. Both chemical and/or physical approaches can be used to enhance the penetration of drug molecules across the skin, the properties of an ideal skin penetration enhancer include the following: (1) it should be odorless and colorless; (2) it should be specific in its mode of action; (3) it should be pharmacologically inert; (4) it should be compatible with drugs and other excipients; (5) it should be chemically and physically stable; (6) it should be non-allergenic, non-irritant and non-toxic; (7) its action should be reversible and (8) it should give a rapid effect for a predictable duration of time, the site of action of the chemical skin penetration enhancers is located in the stratum corneum, chemical enhancers can be divided into two broad categories: Those that change partitioning into the stratum corneum and those that influence diffusion across the stratum corneum skin penetration enhancers may act by one or more of three potential mechanisms according to the lipid-protein-partitioning theory. Firstly, penetration enhancers can alter the intercellular lipid structure between the corneocytes to increase diffusivity. Secondly, they can modify intracellular protein domains within the horny layer. Thirdly, they may increase the partitioning of the drug into the skin tissue penetration enhancers of natural origin with reference to their proposed mechanisms of action, effectiveness to deliver drugs across the skin and their shortcomings. The categories of natural skin penetration enhancers that are discussed include essential oils, isolated terpenes (from essential oils), fixed oils (or fatty acids) and complex polysaccharides, Aloe vera Gel/Juice, Polysaccharides and lectins present in the inner pulp or gel of the leaves are considered to be the most important components, in vitro studies showed that Aloe Vera Gel has drug permeation enhancement properties across the skin. Physiochemical properties such as the calculated octanol-water partition coefficient/drug lipophilicity and molecular weight of the model drug compounds were investigated, and they were found to influence the enhancement properties of the Aloe Vera Gel material. In addition, it was found that a significant proportion of Aloe Vera Gel constituents permeated the skin together with the model drug compound Aloe Vera Gel had a higher permeation enhancement effect on drugs with a higher molecular weight. This was explained by the fact that a drug with a larger molecular weight effectively blocks the permeation routes allowing increased possibility for the drug to interact with the enhancing factor and complex with it prior to being transported across the skin. It was further found that double strength Aloe Vera Gel at a concentration of 3% (w/v) enhanced the permeation of quinine significantly higher when compared to the standard strength, Aloe Vera Gel phytochemicals can be used within-vehicle.
